ES2203392T3 - PHOSPHINIC REDUCTION FROM AZIDAS TO AMINAS. - Google Patents

Abstract

A new process for the preparation of 4,5-diamino shikimic acid derivatives starting from 4-amino-5-azido shikimic acid derivatives is provided. 4,5-diamino shikimic acid derivatives and its pharmaceutically acceptable addition salts are potent inhibitors of viral neuraminidase.

Description

Phosphine reduction of azides to amines.

The present invention relates to a process for the preparation of acid derivatives 4,5-diamino shichemical, especially for ethyl preparation (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate and its pharmaceutically acceptable addition salts of derivatives of acid 4-amino-5-azido shichemical, especially ethyl (3R, 4R, 5S) -4-acetamido-5-azido-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate.

A similar procedure is described in WO 96/26933.

Acid derivatives 4,5-diamine shichemical, especially ethyl (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethyl-propoxy) -1-cyclohexene-1-carboxylate and its pharmaceutically acceptable addition salts are potent viral neuroaminidase inhibitors (J.C. Rohloff et al., J. Org. Chem. 63, 1998, 4545-4550; WO 98/07685).

It is known in the state of the art a ethyl reduction (3R, 4R, 5S) -4-acetamido-5-azido-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate to ethyl (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate by hydrogenation in the presence of a nickel catalyst Raney (J.C. Rohloff et al, loc. Cit.).

It was found that the starter compound "5-azido" since its previous synthesis always contains a small amount of the compound "2,5-diazido" formed by the formal addition of double bond hydrazoic acid. In the course of the hydrogenation the azido group at position 5 becomes easily in the desired amino group, the group transformation azido in position 2 is however very slow. Therefore it form an intermediate "2-azido-5-amino" which was "positive Ames" and therefore suspicious of Be mutagenic.

This intermediate cannot be separated so satisfactory with common purification techniques. The problem neither can it be overcome by prolonging time of hydrogenation for the "double hexene cycle link "that will become hydrogenated too.

The objective of the present invention therefore is to provide the process that does not involve these difficulties known in the state of the art, for example, a process that allow easy access to the target product in a quality Excellent.

It was found that this goal could be performed surprisingly by reduction with a phosphine of in accordance with claim 1.

The present invention therefore relates to a procedure for the preparation of an acid derivative 4,5-diamine shichemical of the formula

one

and a pharmaceutically acceptable addition salt respective in where

R1 is an alkyl group optionally replaced,

R2 is an alkyl group and

R 3 and R 4, independently of each other, they are H or a protective amino group, with the proviso that R3 and R 4 are not both H,

characterized by the reduction of a acid derivative 4-amino-5-azido-shichemical of formula

two

wherein R 1, R 2, R 3 and R 4 they have the meaning as summarized above with a phosphine in presence of a catalytic amount of an acid and, if necessary, by further transformation into an acceptable addition salt pharmaceutically

The term alkyl in R1 has the meaning of a straight or branched chain alkyl group of 1 to 20 carbon atoms, conveniently from 1 to 12 carbon atoms. Examples of such alkyl groups are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, tert-butyl, pentyl and its isomers, hexyl and its isomers, heptyl and its isomers, octyl and its isomers, nonyl and its isomers, decyl and its isomers, undecyl and its isomers and Dodecyl and its isomers.

This alkyl group can be substituted with one or more substituents as defined for example in WO 98/07685. The suitable substituents are C_ {1-6} -alkyl (as defined before), C 1-6 -alkenyl, C 3-6 -cycloalkyl, hydroxy, C 1-6 -alkoxy, C 1-6 -alkoxycarbonyl, F, Cl, Br, J. The preferred meaning for R1 is 1-ethylpropyl.

R2 is a straight chain alkyl group or branched from 1 to 12 carbon atoms, conveniently from 1 to 6 carbon atoms as exemplified above.

The preferred meaning for R2 is ethyl.

The term amine protecting group in R3 and R 4 refers to any protecting group used conventionally and known in the art. These are described, by example, in "Protective Groups in Organic Chemistry", Theodora W. Greene et al., John Wiley & Sons Inc., New York, 1991, p. 315-385. Appropriate amine protecting groups are they also give in, for example, WO 98/07685.

Preferred amine protecting groups are groups alkanoyl, more preferably C 1-6-lower alkanoyl, pentanoyl, butanoyl (butyryl), propanoyl (propionyl), ethanoyl (acetyl) and methanoyl (formido). The preferred alkanoyl group and therefore the preferred meaning for R3 is acetyl and for R 4 H.

Acid derivative 4-amino-5-azido-shichemical of formula (II) as starting compounds of the present Process of the invention are accessible as described in J.C. Rohloff et al., Loc. cit and in WO 98/07685.

Acid derivative 4-amino-5-azido-shichemical preferred of formula (II) is (3R, 4R, 5S) -4-acetamido-5-azido-3- (1-ethylpropoxy) -1-cyclohexen-1-carboxylate of ethyl. Thus the 4,5-diamino acid derivative Preferred shichemical of formula (I) is the carboxylate of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate of ethyl and the (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate ethyl phosphate (1: 1).

The phosphine used can be defined by the General Formula

IIIP (R 5) 3

where R 5 is I rent.

R5 is conveniently a group of C 1-8 - straight or branched chain alkyl as defined before.

Phosphines that can be used properly they are trioctyl phosphine, triisobutyl phosphine, tri-n-butyl phosphine and triethyl phosphine The most preferred phosphine is tri-n-butyl phosphine.

Phosphine is a rule added in quantities stoichiometric or in a slight excess of up to 1.05 equivalents relative to the acid derivative 4-amino-5-azido-shichemical of formula (II).

Typically the reduction is carried out in a polar protic solvent such as alcohols, preferably in a aqueous ethanol or an aqueous tetrahydrofuran, more preferably in aqueous ethanol

The reaction temperature depends mainly of the phosphine used but as a rule is in the range of minus 20 ° C to 30 ° C, preferably between 0 and 25 ° C.

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It may be favorable to carry out the reaction at two temperature levels, having with this the range of lower temperature given before for phosphine addition and subsequently having a temperature slightly higher than the room temperature to complete the reaction.

As a specific modality of this invention it was found that the catalytic amounts of an acid present during conversion suppress ester hydrolysis that on the other hand it takes place in a small area of some percentage and Due to this it leads to an undesirable impurity.

The appropriate acid is a carboxylic acid, conveniently acetic acid. Acetic acid is usually add in the form of glacial acetic acid in amounts catalytic 0.5mol% to 3.0mol% in relation to the acid derivative 4-amino-5-azido Shichemical of formula (II).

The process as a rule is terminated after 3 to 6 hours

Then the final elaboration of the mixture reaction can be carried out by applying methods known to the art expert Conveniently the reaction mixture is concentrated in vacuo, preferably after stabilization with ≤ 5 mol% acetic acid, concentrated in vacuo.

While the acid derivative 4,5-diamine shichemical can be isolated, for example, by evaporation and crystallization it is maintained, preferably, for example an ethanolic solution and then additionally transformed into the pharmaceutically addition salt acceptable following the methods described in J.C. Rohloff et al., J. Org. Chem. 63, 1998, 4545; WO 98/07685).

The term "acid addition salts pharmaceutically acceptable "encompasses salts with inorganic acids and organic, such as hydrochloric acid, hydrobromic acid, acid nitric, sulfuric acid, phosphoric acid, citric acid, acid formic, fumaric acid, maleic acid, acetic acid, acid succinic, tartaric acid, methanesulfonic acid, acid p-toluenesulfonic and the like.

Salt formation is performed with methods that they are known per se and are familiar to any expert in the art. Not only salts with acids come into consideration inorganic, but also salts with organic acids. Examples of These salts are hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, maleates, succinates, methanesulfonates, p-toluenesulfonates, and Similar.

The acid addition salt pharmaceutically Acceptable acceptable is 1: 1 salt with phosphoric acid that can preferably, in ethanolic solution, at a temperature between -20ºC and 60ºC.

The following examples illustrate the invention with greater detail without limiting it.

1. Preparation of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethyl-propoxy) -1-cyclohexen-1-carboxylate of ethyl

In a 1000 ml glass reactor purged with nitrogen and equipped with a mechanical stirrer, condenser and a 250 ml drip funnel 50.0 g (0.147 mol) of (3R, 4R, 5S) -4-acetamido-5-azide-3- (1-ethylpropoxy) -1-cyclohexen-1-carboxylate of ethyl. 300 ml of ethanol, 50 ml of water and 0.09 g were added of acetic acid. To the resulting clear solution was added of continuous mode at a temperature of 5ºC (+/- 5ºC) for a period 30-90 minutes, 31.4 g (0.155 mol) of tributylphosphine dissolved in 150 ml of ethanol. Light bass jacket cooling (about 3 ° C) the temperature of reaction at this temperature. The feeder was washed with 20 ml of ethanol. The clear reaction mixture was stirred for 90 minutes more at 5ºC (+/- 5ºC) under slight cooling of the jacket. TO then the temperature rose within 30-60 minutes up to 20-25ºC and s stirred the solution for another 3 hours (with generation of nitrogen).

After finishing the reaction (HPLC control) 0.18 g of acetic acid was added to the clear solution. Then I know concentrated the mixture under reduced pressure (300 to 50mbar) to a maximum temperature of 60ºC and a maximum jacket temperature of 75 ° C close to dryness. The oily residue was diluted (80-100 ml) with 160 ml of ethanol, then concentrated the resulting solution again following the method as It has been indicated before. The oily residue was dissolved in ethanol until a volume of 250 ml. The aqueous content of this solution is determined by titration of KF (Karl Fischer) as being less than 1.0% by weight%. Yield: 44.4g (97% area by HPLC) of the product of the title in ethanolic solution.

2. Preparation of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1- ethylpropoxy) -1-cyclohexen-1-carboxylate Phosphate (1: 1)

In a 1000 ml glass reactor purged with nitrogen and dry equipped with a mechanical stirrer, a condenser, and a 500 ml drip funnel 17.0 g of ortho acid was dissolved phosphoric (85% in water) in 400 ml of ethanol and the resulting clear solution up to 50-55 ° C. TO then 250 ml of solution was added under stirring Etanolic obtained from Example 1 and containing 0.147 mol from (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate of ethyl. After quick addition (10-15min) of two thirds (about 160 ml) of the total volume of this solution the addition was stopped and the clear solution was seeded supersaturated with 0.2 g of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate ethyl phosphate (1: 1) previously obtained. Immediately after crystallization began. The dense suspension was stirred resulting for 45-60 minutes at 50-55 ° C. Then the solution was added slowly remaining amine (45-60 minutes) to the suspension at 50-55 ° C. The feeder was washed with 20 ml of ethanol. Then the dense suspension was cooled continuously to 12-20ºC in about 4 hours (speed of cooling = 10 ° C / h). To complete the crystallization, stirring continued at 12-20 ° C for 2 ± 1 additional hours It was isolated (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate ethyl phosphate (1: 1) by pressure filtration (0.3 bar nitrogen overpressure, Dacron® filter cloth). The crystalline product was washed twice with 240 ml of acetone and two times with 300 ml of n-heptane at temperature environment. It was dried under vacuum (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexen-1-carboxylate ethyl phosphate (1: 1) ((mbar) at maximum temperature of 50 ° C to constant weight.

Yield: 54-55 g (88-91%) of the product of the heading in the form of colorless needles with a test of = 99% by weight (sum of impurities <0.5% by weight, simple impurities? 0.1% by weight).

Comparative example one

Preparation of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethyl-pro-poxy) -1-cyclohexen-1-carboxylate ethyl (hydrogenation with Ra-Ni)

100 g (0.295 mol) of (3R, 4R, 5S) -4-acetamido-5-azido-3- (1-ethylpropoxy) -1-cyclohexen-1-carboxylate of ethyl in 800 ml of ethanol and placed in a steel autoclave of 2 liters together with 34 g of Nickel Raney (Degussa) in 200 ml of ethanol. The autoclave was closed and washed twice with nitrogen and then it was fixed under 2 bar hydrogen pressure. Hydrogenation  it took place at a temperature of 20-25ºC low mechanical stirring at 1000 rpm until, after reacting all the starting material, also the content of the "intermediate of 2-azido-5-amino " It was ≤ 0.01% area (CG measurement) which was around 5-8 hours. However it was found that due to this overhydrogenation "the double bond of cyclohexene" is He also returned hydrogenated.

The content of the cyclohexane derivative respective was therefore 3-6% area (CG measurement).

The final elaboration was carried out with the addition of 52 ml of cyclopentene and 1 hour of subsequent stirring under nitrogen atmosphere. Then the mixture was pressurized reactive through a pressure filter (overpressure of N 2 of 2 bars). The residue in the reactor was then diluted with 400 ml of ethanol followed by pressure filtration. The filtered combined (about 1250 ml) were concentrated until solution of 500 ml and contained about 70-80 g of the product of the heading.

Comparative example two

Preparation of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethyl-pro-poxy) -1-cyclohexen-1-carboxylate ethyl phosphate (1: 1)

In a dry and purged 2000 ml glass reactor with nitrogen, equipped with mechanical stirrer, a condenser, and a 500 ml drip funnel, 33.0 g of ortho acid were dissolved phosphoric (85% in water) in 1400 ml of ethanol and the resulting clear solution up to 50-55 ° C. TO 500 ml of solution was added with stirring ethanol obtained from comparative example l and containing about 224 mmol of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate of ethyl. After quick addition (10-15min) of two thirds (about 330 ml) of the total volume of this solution the addition was stopped and the cleaned solution was seeded supersaturated with 0.4 g of (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate ethyl phosphate (1: 1) previously obtained. Immediately after Crystallization began. The resulting dense suspension was stirred for 45-60 minutes at 50-55 ° C. Then the remaining amine solution was added slowly (45-60 minutes) to the suspension at 50-55 ° C. The feeder was washed with 20 ml of ethanol. The suspension was then cooled continuously dense to -20 ° C in about 6 to 7 hours. To complete it crystallization stirring was continued at -20 ° C. (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate ethyl phosphate (1: 1). It was isolated by filtration and washed twice with 480 ml of acetone (room temperature).

The crystalline product was resuspended in 2600 ml of acetone for 3 hours at 24 ° C-28 ° C, filtered, washed twice with 400 ml of acetone (room temperature) and two times with 600 ml of n-heptane (temperature environment). (3R, 4R, 5S) -4-acetamido-5-amino-3- (1-ethylpropoxy) -1-cyclohexene-1-carboxylate of ethyl phosphate (1: 1) dried under vacuum (\20 mbar) at temperature of 25º-28ºC until constant weight.

Yield: 73-90 g (80-85%) of the product of the heading in the form of colorless needles with a 99% weight test. The content of "overhydrogenated" cyclohexane derivative was still among 0.5 and 2.0% area. (CG measurement).

Claims (9)

1. Process for the preparation of a derivative of 4,5-diamino shichemical acid of formula 3 and a pharmaceutically acceptable addition salt from East where R1 is a substituted alkyl group optionally R2 is an alkyl group and R 3 and R 4, independent of each other they are H or an amino protection group, with the proviso that neither R 3 or R 4 are H characterized by the reduction of a 4-amino-5-azido-shichemical acid derivative of the formula 4 wherein R 1, R 2, R 3 and R 4 it has the meaning as summarized above with a phosphine in presence of a catalytic amount of an acid, and if it is necessary, additional transformation into an acceptable addition salt pharmaceutically 2. Process according to claim 1, characterized in that the phosphine used has the formula IIIP (R 5) 3 where R 5 is I rent. 3. Process according to claim 2, characterized in that tri-n-butylphosphine is used. 4. Process according to claim 1 to 3, characterized in that the conversion takes place in a polar protic solvent at a temperature of -20 ° C to 30 ° C. 5. Process according to claim 4, characterized in that the polar protic solvent is aqueous ethanol. 6. Process according to claim 1 to 5, characterized in that the process is conducted in the presence of a catalytic amount of a carboxylic acid. 7. Process according to claim 6, characterized in that the process is conducted in the presence of a catalytic amount of 0.5mol% to 3.0mol% acetic acid. 8. Process according to claims 1 to 7, characterized in that the derivative of 4-amino-5-azido-shichemical acid of formula (II) is (3R, 4R, 5S) -4-acetamido-5-azido-3 - Ethyl (1-ethylpropoxy) -1-cyclohexene-1-carboxylate.

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9. Process according to claims 1 to 7, characterized in that the derivative of the 4-amino-5-azido-shichemical acid of formula (II) is (3R, 4R, 5S) -acetamido-5-azido-3- ( Ethyl 1-ethylpropoxy) -1-cyclohexene-1-carboxylate Phosphate (1: 1).